PEAK1 promotes prostate cancer progression and docetaxel resistance by mediating the polarization of tumor-associated macrophages.

backgroundPseudopodium-enriched atypical kinase 1 (PEAK1) expression is altered in multiple human malignancies and promotes tumor proliferation, metastasis, and chemical therapy resistance. Here, we aimed to investigate the role and mechanisms of PEAKs in prostate cancer (PCa) progression and docetaxel resistance.

methodsThe expression of PEAKs in PCa cells (LNCaP, PC3, DU145, and VCaP) was analyzed. PEAK1 knockdown or overexpression models were established in DU145, LNCaP, and PC3 cells. Functional assays were conducted to measure cell proliferation via CCK-8, EdU staining, and colony formation assays; cell migration was tested via transwell assays; and epithelial-to-mesenchymal transition (EMT) was detected via Western blotting. The sensitivity of PCa cells to docetaxel (DTX) or enzalutamide was tested via the CCK8 assay. A coculture model of PCa cells and THP-1 cells was used to test the interaction between PCa cells and THP-1 macrophages. Furthermore, the effects of PEAK1 on PCa cell growth were investigated in a xenograft model in nude mice. Western blot analysis was used to validate the expression levels of HIF-1α, PD-L1, STAT3, and NF-κB p65. Immunohistochemistry was used to detect infiltration of macrophages and T cells in the tumors.

resultsPEAK1 expression was significantly elevated in DU145 and PC3 cells after long-term treatment with DTX. PEAK1 upregulation promoted cell proliferation, migration, EMT, and growth in nude mice, whereas PEAK1 knockdown reversed these effects. PEAK1 overexpression attenuated PCa cell sensitivity to DTX and enzalutamide, as evidenced by enhanced cell proliferation and reduced apoptosis. Furthermore, PEAK1-overexpressing PCa cells induced CCL2 and IL-6 production and promoted "M2" polarization of macrophages (M2-Mφ). M2-Mφs enhanced PCa cell proliferation and migration and attenuated DTX sensitivity. In vivo assays revealed that PEAK1 upregulation enhanced PCa cell growth and M2-Mφ infiltration but reduced CD8 + T-cell infiltration. Mechanistically, TGF-β, possibly produced by "M2" macrophages, induced PEAK1 upregulation. PEAK1 overexpression led to increased expression of HIF-1α and increased STAT3 and NF-κB pathway activation in PCa cells.

conclusionsPEAK1 plays an oncogenic role in prostate cancer by promoting cell metastasis, reducing docetaxel and enzalutamide sensitivity, and mediating "M2" polarization of macrophages by activating the HIF-1α/STAT3/NF-κB pathway.